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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2019

Open Access 01-12-2019 | Human Immunodeficiency Virus | Research article

Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice

Authors: Saumi Mathews, Amanda Branch Woods, Ikumi Katano, Edward Makarov, Midhun B. Thomas, Howard E. Gendelman, Larisa Y. Poluektova, Mamoru Ito, Santhi Gorantla

Published in: Molecular Neurodegeneration | Issue 1/2019

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Abstract

Background

Microglia are the principal innate immune defense cells of the centeral nervous system (CNS) and the target of the human immunodeficiency virus type one (HIV-1). A complete understanding of human microglial biology and function requires the cell’s presence in a brain microenvironment. Lack of relevant animal models thus far has also precluded studies of HIV-1 infection. Productive viral infection in brain occurs only in human myeloid linage microglia and perivascular macrophages and requires cells present throughout the brain. Once infected, however, microglia become immune competent serving as sources of cellular neurotoxic factors leading to disrupted brain homeostasis and neurodegeneration.

Methods

Herein, we created a humanized bone-marrow chimera producing human “microglia like” cells in NOD.Cg-PrkdcscidIl2rgtm1SugTg(CMV-IL34)1/Jic mice. Newborn mice were engrafted intrahepatically with umbilical cord blood derived CD34+ hematopoietic stem progenitor cells (HSPC). After 3 months of stable engraftment, animals were infected with HIV-1ADA, a myeloid-specific tropic viral isolate. Virologic, immune and brain immunohistology were performed on blood, peripheral lymphoid tissues, and brain.

Results

Human interleukin-34 under the control of the cytomegalovirus promoter inserted in NSG mouse strain drove brain reconstitution of HSPC derived peripheral macrophages into microglial-like cells. These human cells expressed canonical human microglial cell markers that included CD14, CD68, CD163, CD11b, ITGB2, CX3CR1, CSFR1, TREM2 and P2RY12. Prior restriction to HIV-1 infection in the rodent brain rested on an inability to reconstitute human microglia. Thus, the natural emergence of these cells from ingressed peripheral macrophages to the brain could allow, for the first time, the study of a CNS viral reservoir. To this end we monitored HIV-1 infection in a rodent brain. Viral RNA and HIV-1p24 antigens were readily observed in infected brain tissues. Deep RNA sequencing of these infected mice and differential expression analysis revealed human-specific molecular signatures representative of antiviral and neuroinflammatory responses.

Conclusions

This humanized microglia mouse reflected human HIV-1 infection in its known principal reservoir and showed the development of disease-specific innate immune inflammatory and neurotoxic responses mirroring what can occur in an infected human brain.
Appendix
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Metadata
Title
Human Interleukin-34 facilitates microglia-like cell differentiation and persistent HIV-1 infection in humanized mice
Authors
Saumi Mathews
Amanda Branch Woods
Ikumi Katano
Edward Makarov
Midhun B. Thomas
Howard E. Gendelman
Larisa Y. Poluektova
Mamoru Ito
Santhi Gorantla
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2019
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-019-0311-y

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